Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide and metabolites after a 72-h continuous infusion in patients with soft tissue sarcoma.

摘要: Objective: The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide its main metabolites 2- 3-dechloroethylifosfamide 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. Methods: Twenty received 9 or 12 g/m2 administered as a 72-h continuous intravenous infusion. pharmacokinetic model was built sequential manner, starting covariate-free progressing to covariate aid generalised additive modelling. Results: addition covariates weight, body surface area, albumin, serum creatinine, urea, alkaline phosphatase lactate dehydrogenase improved prediction errors model. Typical pretreatment (mean ± SEM) initial clearance 3.03±0.18 l/h volume distribution 44.0±1.8 l. Autoinduction, dependent on levels, characterised by an induction half-life 11.5±1.0 h 50% maximum at 33.0±3.6 µM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P=0.019) observed between exposure orientational disorder, neurotoxic side-effect. No haematological toxicities could be this population.